Helper T cell differentiation enters a new era: le roi est mort; vive le roi!

Abstract

In the dark ages of T cell biology, we considered two fates for differentiated CD4+ T cells: T helper (Th)1 and Th2 cells. Now we know that the reality is much more complex and interesting. The newest Th cell subset produces the cytokine IL-17. New evidence shows that the IL-17-related cytokine IL-25 is essential for Th2 responses in two infectious disease models.

Figure 1.

Th cell differentiation: how many flavors? On pathogen challenge, CD4⁺ T cells will differentiate into either IFN-γ–producing Th1 cells or IL-4–producing Th2 effector cells, which directly cross-regulate each other. Th17 cells have recently been added to the list of Th effector cells. Two new reports now suggest that the IL-17 family member IL-25—possibly produced by a population of T cells in the gut mucosa—induced Th2 cell differentiation during helminth infection. The target of IL-25 may be a nonlymphoid c-kit⁺ population, which produces IL-4 and in turn enhances Th2 cell differentiation by CD4⁺ T cells. In addition, IL-25 may have a direct role in inhibiting both Th1- and Th17-producing cells during helminth infection in order to limit the inflammatory response. The extent to which IL-25–producing T cells are a distinct Th lineage (Th25) or if IL-25 production is a feature of many Th2 cells will need further investigation.